Process for the preparation of 1,5-dideoxy-1,5-imino hexitols from oximes or imines

ABSTRACT

A process for the preparation of 1,5-dideoxy-1,5-imino hexitols of a hexose sugars from novel hydroxyl protected oxime intermediates. The process includes formation of a lactam which is reduced to the hexitol. The hexitols are useful as drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Provisional Application No.60/193,554, filed Mar. 31, 2000.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

None.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to multistep synthesis of a1,5-dideoxy-1,5-imino hexitol from a ketoaldonic acid methyl ester of ahexose sugar with protected hydroxyl groups and to novel intermediates.In particular the present invention relates to processes which enablethe production of novel intermediates to the hexitol and in particular,a ketoaldonic acid methyl ester oxime or alkylimine, which forms thering structure of the hexitol by alternate routes.

(2) Description of Related art

Over the last three decades there has been a continued interest innatural and synthetic imino-sugars because of their high potency asglycosidase inhibitors ((a) Grabner, R. W., et al., U.S. Pat. No.5,695,969; (b) Boshagen, H., et al., U.S. Pat. No. 4,940,705; (c)Shilvock, J. P., et al., Tetrahedron Lett., 37 8569-8572 (1996); (d)Rajanikanth, D. B., et al., J. Chem. Soc. Perkin Trans. I 2151-2152(1992); (e) Hussain, A., et al., Tetrahedron, 49 2123-2130 (1993); (f)Defoin, A., et al., Tetrahedron Lett. 34 4327-4330) (1997); (g) Defoin,A., et al., Tetrahedron 53 13769-13782 (1997); (h) Defoin, A., et al.,Tetrahedron Lett. 35 5653-5656 (1994); (i) Fleet, G. W. J., et al.,Tetrahedron lett. 29 2871-2874 (1988); (j) Fleet, G. W. J., et al.,Tetrahedron 45 327-336 (1989); (k) Takahashi, S., et al. Chem. Lett.21-24 (1992); (1) Takahashi, S., et al., J. Chem. Soc., Perkin Trans. I,607-612 (1997); (m) Hendry, D., et al., Tetrahedron Lett. 28 4597-4600(1987); (n) Hendry, D., et al., Tetrahedron Lett. 28 4601-4604 (1987);(o) Straub, A., et al., J. Org. Chem. 55 3926-3932 (1990); Delinck, D.L., et al., Tetrahedron Lett. 31 3093-3096 (1990); (r) Look, G. C., etal., Acc. Chem. Res. 26 182-190 (1993); (s) Kajimoto, T., et al., J. Am.Chem. Soc. 113 6678-6680 (1991)). Glycosidases catalyze the hydrolysisof glycosidic linkages and are the key enzymes in the degradation ofcomplex carbohydrates. One of their main metabolic roles is theconversion of complex non-absorbable carbohydrates into absorbable mono-or oligosaccharides (Truscheit, E., et al., Angew. Chem. Int. Ed. Engl.20 744-761 (1981)). The rapid action of these enzymes can lead, however,to undesirable elevations in blood glucose in diabetes. Iminosugars havebeen shown to act as glycosidase inhibitors and to retard and regulatethe intestinal carbohydrate digestion. They are therefore excellent drugcandidates for diabetes therapy (Liu, P. S., U.S. Pat. No. 4,634,765(1987)). An even more exciting potential use of iminosugars is in thetreatment of cancer and viral diseases (Rohrschneider, L. R., et al.,U.S. Pat. No. 4,837,237 (1989)). It has been shown that modification ofoligosaccharide structures may alter metastatic capacity of cancer cellsand 1,5-diimino-1,5-dideoxyglucitol (deoxynojirimycin) (1) (Tsuruoka,T., et al., U.S. Pat. No. 5,250,545 (1993)) swainsonine (2) (Dennis, J.W., Cancer Res. 46 5131-5136 (1986)) and castanospermine (3) (Humphries,M. J., et al., Cancer Res. 46 5215-5222 (1986)) (FIG. 1.) can markedlyinhibit metastasis of cancer cells. They might, therefore, be used forthe effective treatment of cancer.

N-Butyl-deoxynojirimyciin shows excellent activity against herpes virus(Jacob, G. S., et al., U.S. Pat. No. 4,957,926 (1990)) whilst having lowcyto-toxicity and no inhibitory effect on the growth of normal cells.The greatest prospect for the use of iminosugars as drugs is probablyfor the treatment of AIDS. Glycosidase inhibitors prevent the processingof N-linked complex oligosaccharides. This results in the disruption ofthe synthesis of viral coat glycoproteins such as the critical onecalled gp120. This supposedly leads to the loss of recognition by theCD-4 receptor of the target cell with concomitant reduction of syncytiaformation resulting in the reduction of virus infectivity and theinhibition of viral replication (Walker, B. D., et al., Proc. Natl.Acad. Sci. USA 84 8120-8124 (1987); Karpas, A., et al., Proc. Natl.Acad. Sci. USA 85 9229-9233 (1988); Fleet, G. W. J., et al., FEBS Lett.237 128-132 (1988)). Clinical trials have been launched forN-Butyl-deoxynojirimycin (Rohrschneider, L. R., U.S. Pat. No. 5,643,888(1997)). The iminosugars that have been the most investigated aredeoxynojirimycin ((a) Schroder, T., et al., U.S. Pat. No. 4,806,650(1989); (b) Koebernick, W., U.S. Pat. No. 4,611,058 (1986); (c)Anzeveno, P. B., et al. U.S. Pat. No. 5,227,479 (1993); (d) Anzeveno,U.S. Pat. No. 4,908,439 (1990); (e) Tsuda, Y., et al., Heterocycles, 2763-66 (1988); (f) Inouye, S., et al., Tetrahedron 23 2125-2144 (1968);(g) Vasella, A., et al., Helv. Chim. Acta 65 1134-1144 (1982); Ikota,N., et al., Heterocycles 46 637-643 (1997); (i) Paulsen, H., et al.,Chem. Ber 100 802-815 (1967); (j) Rudge, A. J., et al., Angew. Chem.Int. Ed. Engl. 33 2320-2322 (1994); (k) Behling, J., et al., Synth.Commun. 21 1383-1386 (1991); (1) Kinast, G., et al., Angew. Chem. Int.Ed. Engl. 20 805-806 (1981); (m) Pederson, R. L., et al., TetrahedronLett. 29 4645-4648 (1988); (n) Osten, C. H., et al., J. Am. Chem. Soc.111 3924-3927 (1989)) and its N-alkyl analogues (Grabner, R. W., et al.,U.S. Pat. No. 5,610,039 (1997); U.S. Pat. Nos. 4,806,650; 4,611,058;4,940,705).

The chemical synthesis of nojirimycin derivatives are generally tooinvolved and not suitable for commercial applications. Thechemo-microbiological method patented by Grabner (U.S. Pat. Nos.5,695,969; 5,610,039)) provides an elegant method for transforming asugar into its imino-derivative by reductive animation of a 5-ketoaldose obtained by bacterial oxidation of glucose. The method is inparticular however, not applicable to the D-galacto derivatives of thepresent invention.

Other related patents are: U.S. Pat. Nos. 5,227,479, 5,250,545,5,695,969, 4,957,926, 4,908,439 and 4,634,765.

SUMMARY OF INVENTION

The present invention relates to a process for the preparation of analdonic-5-oxime methyl ester of a hexose sugar which has protectedhydroxyl groups which comprises:

(a) reacting a ketoaldonic acid methyl ester of the sugar with theprotected hydroxyl groups with a an alkylamine or hydroxylamine acidsalt in an organic solvent with a tertiary amine to react with an acidgenerated in the reaction at a temperature of about 60° C. or less toproduce the oxime methyl ester in a reaction mixture; and

(b) separating the oxime methyl ester from the reaction mixture.

The present invention also relates to a a process for the preparation ofmethyl 2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime which comprises:

(a) reacting methyl 2,3,4,6-tetra-O-acetyl-5-hexulosonic acid methylester with hydroxylamine hydrochloride in a first organic solvent with atertiary amine to react with an acid generated in the reaction mixtureat a temperature of between about −10 and 60° C.;

(b) introducing the reaction mixture into water containing ice;

(c) extracting the oxime from the reaction mixture with a second organicsolvent for the oxime; and

(d) separating the oxime from the second solvent.

Further, the present invention relates to a process for the preparationof an aldonic acid hydrazide oxime of a hexose sugar with protectedhydroxyl groups which comprises:

(a) reacting an aldonic acid-5-oxime or alkylimine methyl ester of thesugar with the protected hydroxyl groups with anhydrous hydrazine in anorganic solvent at less than about 30° C. to produce the hydrazideoxime; and

(b) separating the hydrazide oxime of the sugar from the reactionmixture.

The present invention also relates to a process for the preparation ofthe 5-lactam of a hexose sugar which has hydroxyl groups whichcomprises:

(a) reacting an aldonic acid methyl ester oxime or alkylimine of thesugar with the protected hydroxyl groups with hydrogen and ahydrogenation catalyst in an acidic solvent at a temperature betweenabout 20 and 80° C. and at a pressure between about 200 and 400 psi ofthe hydrogen to produce the acid lactam of the sugar in a reactionmixture; and

(b) separating the lactam from the mixture.

The present invention also relates to a process for the preparation of a1,5-imino-1,5-dideoxyhexitol which comprises:

(a) reacting a 5-imino-5-deoxyhexonic acid lactam of a hexose sugarwhich has hydroxyl groups with a reducing agent in a solvent at atemperature between about 0° and 80° C. to produce the1,5-imino-1,5-dideoxyhexitol in a reaction mixture; and

(b) separating the imino 1,5-imino-1,5-dideoxyhexitol from the reactionmixture.

The present invention also relates to a process for the preparation of1,5-imino,-1,5-dideoxy hexitol with or without the protected hydroxylgroups which comprises:

(a) reacting an acid ester or a hydrazide of a 5-hexulosonic acid oximeor alkylimine with or without the protected hydroxyl group with hydrogenand a hydrogenation catalyst in an acidic solvent at a temperaturebetween about 20 and 80° C. and a pressure between about 200 and 400 psito form a 5-imino-5-deoxyaldonic acid lactam; and

(b) reducing, if necessary deprotecting the hydroxyl groups, the lactamwith a reducing agent to form the 1,5-dideoxy-1,5-imino hexitol.

The present invention relates to a process for the preparation of1,5-imino,-1,5-6-trideoxy hexitol as a product which comprises:

(a) reacting methyl-2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime withhydrogen and a hydrogenation catalyst at a temperature between about 20and 80° C. and a pressure between about 200 and 400 psi in an acidicsolvent to form a 1,5,6-triacetoxy acid lactam;

(b) reducing and deacetylating the lactam with a reducing agent to formthe 1,5-imino hexitol.

The present invention relates to a process for producing a 1,5-iminohexitol which comprises:

(a) reacting an aldonic acid hydrazine-5-oxime or alkylimine with areducing agent in an organic solvent at a temperature between about 20and 80° C. to produce the 1,5imino hexitol in a reaction mixture; and

(b) separating the 1,5-imino hexitol from the reaction mixture.

The present invention relates tomethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime;methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime;tri-O-acetyl-5-amino-5,6-dideoxy-D-gluconic acid lactam;methyl-2,3,4,6-tetra-O-acetyl-L-xylo-5-hexulosonic acid hydrazide oxime;and L-xylo-5-hexulosonic acid hydrazide.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a drawing showing the schematic reactions of Examples 1 and 2.The numbers are for the structures of the compounds of these Examples.

FIG. 2 is a drawing showing the schematic reactions of the reactions ofExamples 3 to 6. The numbers are for structures of the compounds ofthese Examples.

FIG. 3 is a drawing showing the reactions where an oxime group isreplaced with an imino alkyl group.

FIG. 4 is a drawing showing the reaction of the hexitol with an aldehydeto produce an alkyl group on the nitrogen.

DESCRIPTION OF PREFERRED EMBODIMENTS

In particular, the present invention relates tomethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime 5(FIG. 1) as an intermediate for the synthesis of D-dideoxy galactonojirimycins 7. The present invention provides a method for thepreparation of 1,5-imino-1,5-dideoxy and 1,5,6-triteoxy alditols withthe D-galacto configurations starting from β-glactosides via hexulosonicacid oximes which have not been reported before now. The procedure isespecially valuable because of its high stereoselectivity andstraightforwardness. The key steps are the reduction of the oximederivatives to the lactams which is then further reduced to the targetcompounds. The C6 position can be deoxygenated during the reduction ifit bears an acetoxy group. The trideoxy imino sugars are then produced.Deacetylation prior to oxime reduction gives the dideoxy compounds.

The present invention provides a simple access to D-galactonojirimycinsfrom the new oxime intermediate methyl2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime 5. The methodalso allows access to the 5-amino-5-deoxy-D-galacturonic acid 5-lactams.This also is not known before now although the gluco-isomer has beenmade by the oxidation of nojirimycin (Kajimoto, T., et al., J. Am. Chem.Soc. 113 6187-6196 (1991)). In this method, the ketoaldonic acid methylester is converted to the previously unreported oxime which is thenreduced to the amine which cyclizes to give the lactam. The lactam isreduced to the imino sugar by borane or a metal hydride reagent. (Scheme1). Despite the formation of both the cis- and trans oximes, noL-derivatives are formed Reduction of the peracetylated oxime leads todeoxygenation of the 6 position to give the tri-deoxydiiminoalditol(dideoxy-D-galacto-nojirimycin 4).

EXAMPLE 1

Methyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime. 5 Theketoaldonic acid 4 (7 g, 18.61 mmol) was dissolved in pyridine (16 ml)and the solution cooled to 0° C. Hydroxylamine hydrochloride (2 g, 28.77mmol) was then added and the solution stirred at 0° C. for 15 minutesand then for another 2 hours at room temperature. The mixture was pouredonto ice and water and then extracted three times with chloroform. Thecombined chloroform layers were subsequently washed with water, driedwith Na₂SO₄ and then evaporated. Crystallization from hot ethanol gavewhite crystals of the oxime (85%) as a mixture of cis-trans isomers: ¹HNMR (CDCl₃) δ isomer 1:1.98 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.08 (s,3H, OAc), 2.15 (s, 3H, OAc), 3.70 (s, 3H, OCH₃), 4.82 (d, 1H, J_(6a,6b)14.6 Hz, H6-a), 5.11 (d, 1H, H6-b), 5.35 (d, 1H, J_(3,4) 1.9 Hz, H-4),5.68 (d, 1H, J_(3,2) 9. 0, Hz, H-2), 5.84 (dd, 1H, H-3); ¹³C NMR (CDCl₃)δ20.2, 20.3, 20.4, 20.5, 52.6, 56.4, 68.7, 69.2, 69.6, 149.9, 167.5,168.9, 169.3, 170.0, 170.3.

EXAMPLE 2

1,5-imino-1,5,6-trideoxy-D-galactito (dideoxy-D-galacto)nojirimycin. 7This was prepared from the oxime 5 (7.4 g, 18.92 mmol) by reduction withhydrogen on palladium in acetic acid. The intermediate amino ester wascyclized to form a lactam 6 that was then reduced by borane. Flashcolumn chromatography using a chloroform-methanol (6:1) mixture gave(dideoxy-D-galacto)nojirimycin 7 (1.5 g, 30%): [α]²³D+27.0° (c 1.3,CHCl₃), lit.+49.0° (c 1, CHCl₃) [20]; ¹H NMR (D₂O) δ1.21 (d, 3H, J_(5,6)6.6 Hz, H-6), 2.73 (t, 1H, J_(1a,1e)=J_(1a,2) 11.9 Hz, H-1a), 3.30 (dd,1H, J_(1e,2) 5.4 Hz, H-1e), 3.37 (m, 1H, H-5), 3.50 (dd, 1H, J_(2,3) 9.6Hz, J_(3.4) 3.1 Hz, H-3), 3.90 (d, 1H, J_(4.5) 3.1 Hz, H-4), 3.91 (ddd,1H, H-2); ¹³C NMR (D₂O) δ14.2, 46.1, 55.0, 64.4, 69.9, 73.1.

Methyl-2,3,4-6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oximes areintermediates for the preparation of di and tri-deoxynojirimycins. Thepresent invention provides a general method for the preparation of1,5-imino-1,5-6,trideoxy alditols with the D-gluco configurationsstarting from the previously unreportedmethyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime 9 (FIG.2). The key steps are the selective reduction of the oxime derivativesto lactams which are further reduced to the target compounds. The C6position can be deoxygenated during the reduction if it bears an acetoxygroup. The trideoxy imino sugars are then produced. Deacetylation priorto oxime reduction gives the dideoxy compounds.

The present invention provides a simple access to D-gluco nojirimycinsfrom the new oxime intermediateMethyl-2,3,4,6-tetra-O-acetyl-L-arabino-5-hexulosonic acid oxime. Themethod also allows access to the 5-amino-5-deoxy-D-glucuronic acidδ-lactams. This also is known from the oxidation of nojirimycin(Kajimoto, T., et al., J. Am. Chem. Soc. 113 6187-6196 (1991)). It is anexcellent glycosidase inhibitor at concentrations 100 times lower thanmost of the other inhibitors tested (Kajimoto, T., et al., J. Am. Chem.Soc. 113 6187-6196 (1991)). In the method we describe here theketoaldonic acid methyl ester is converted to the previously unreportedoxime which is then reduced to the amine which cyclizes to give thelactam. The lactam is reduced to the imino sugar by borane or a metalhydride reagent. (Pathway 1). Despite the formation of both the cis- andtrans oximes, no L-derivatives are formed. Reduction of theperacetylated oxime leads to deoxygenation of the 6 position to give thetri-deoxydiiminoalditol (dideoxy-D-gluco-nojirimycin) 14. Access to the6-hydroxy derivatives was readily achieved by deacetylating the oximewith hydrazine prior to reduction. The deacetylation yielded the acylhydrazide in quantitative yield (Pathway 2).

EXAMPLE 3

Methyl-2,3,4,6-tetra-O-acetyl-D-xylo-5-hexulosonic acid oxime. 9 Theketone 8 (7 g, 18.61 mmol) was dissolved in pyridine (16 ml) and thesolution cooled to 0° C. Hydroxylamine hydrochloride (2 g, 28.77 mmol)was then added and the solution stirred at 0° C. for 15 minutes and thenfor another 2 hours at room temperature. The mixture was poured onto iceand water and then extracted three times with chloroform. The combinedchloroform layers were subsequently washed with water, dried with Na₂SO₄and then evaporated. Crystallization from hot ethanol gave whitecrystals of the oxime 9 (6.9 g, 95%) as a 3:2 mixture of cis-transisomers: Isomer 1: ¹H NMR (CDCl₃) δ1.93 (s, 3H, OAc), 1.94 (s, 3H, OAc),2.00 (s, 3H, OAc), 2.01 (s, 3H, OAc), 3.56 (s, 3H, OCH₃), 4.36 (d, 1H,J_(6a,6b) 12.4 Hz, H6-a), 4.72 (d, 1H, H6-b), 4.99 (d, 1H, J_(3,4) 2.6Hz, H-4) 5.72 (dd, 1H, J_(3,2) 7.8 Hz, H-3), 6.28 (d, 1H, H-2); ¹³ C NMR(CDCl₃) δ20.5, 20.4, 52.8, 61.3, 66.1, 69.5, 69.8, 149.9, 167.3, 169.4,169.5, 170.1; HRMS (M+H⁺) calcd. 392.1193, found 392.1198. Isomer 2:mp=121-122° C.; ¹H NMR (CDCl₃) δ1.88 (s, 3H, OAc), 1.89 (s, 3H, OAc),1.98 (s, 3H, OAc), 2.00 (s, 3H, OAc), 3.56 (s, 3H, OCH₃), 4.82 (s, 2H,H-6), 5.16 (d, 1H, J_(3,4) 2.6 Hz, H-4), 5.62 (d, 1H, J_(3,2) 8.5, H-2),5.78 (dd, 1H, H-3 ); ¹³C NMR (CDCl₃) δ20.5, 20.4, 52.8, 61.3, 66.1,69.5, 69.8, 149.9, 167.3, 169.4, 169.5, 170.1.

EXAMPLE 4

Tri-O-acetyl-5-amino-5, 6-dideoxy-D-gluconic acid lactam. 10 A solutionof oxime 9 (6.9, g, 17.64 mmol) in glacial acetic acid (275 ml),containing 10% Pd/C (2.76 g) was hydrogenated in a Parr reactor under aH₂ pressure of 300-400 psi for 40 hours at 55° C. The reaction mixturewas filtered through celite and washed with ethanol. The solvent wasrotary-evaporated and the lactam 10 (5 g, 100%) was obtained as a lightyellow syrup: [α]²³D70.0° (c 1.56, CHCl₃); ¹H NMR (CDCl₃) δ1.11 (d, 3H,J_(5,6) 6.3 Hz, H-6), 1.94 (s, 3H, OAc), 1.98 (s, 3H, OAc), 2.00 (s, 3H,OAc), 3.51 (m, 1H, J_(4,5) 9.7, Hz, H-5), 4.94 (t, 1H, J_(3,4) 9.7 Hz,H-3), 4.96 (d, 1H, H-2), 5.40 (t, 1H, H-4); ¹³C NMR (CDCl₃) δ18.0, 20.3,20.3, 48.7, 70.6, 70.9, 71.4, 166.7, 169.4, 169.6, 169.8; HRMS (M+H⁺)calcd. 288.1083, found 288.1089.

EXAMPLE 5

1,5-imino-1,5,6-trideoxy-D-glucitol 11 1M BH₃/THF (50 ml, 50 mmol) wasadded under N₂ to a solution of lactam 10 (5 g, 17.41 mmol) in THF (33ml). The mixture was stirred at room temperature for 1.5 hours and thenrefluxed for another 1.5 hour. After cooling to room temperature 9%methanolic HCl (40 ml) was carefully added and the resulting solutionwas refluxed for 30 minutes. The THF was removed by rotary evaporationand the reaction mixture was dissolved repeatedly in methanol, followedby evaporation to remove borates. Water was added to the dry crudeproduct 10 and the solution was passed through an anion exchange resin(Amberlite IR-45 OH-form) and then dried on the rotary evaporator. Toremove the last traces of borates, a solution of 1M NaOH (15 mol) andmethanol (6 ml) were added to the crude product and the mixture wasstirred overnight at room temperature. The methanol was evaporated andthe aqueous solution was lyophilized. A methanolic HCl solution wasadded, which precipitated NaCl while the methanolic solution was dried,to give the product 10 (2.43 g, 95%): [α]²³D+15.5° (c 1.88, H₂O), lit.13.0° (c 1.0, H₂O) [18]; ¹H NMR (D₂O) δ1.25 (d, 3H, J_(5,6) 6.3 Hz,H-6), 2.77 (dd, 1H, J_(1a,1e) 12.4 Hz, J_(1a,2) 11.7 Hz, H-1a), 3.02(dd, 1H, J_(4,5) 10.0 Hz, H-5), 3.23 (dd, 1H, J_(3,4) (dd, 1H, J_(3,4)9.0 Hz, H-4), 3.33 (dd, 1H, J_(1e,2) 5.1 Hz, H-1e), 3.31 (dd, 1H,J_(2,3) 9.2 Hz, H-3), 3.63 (ddd, 1H, H-2); ¹³C NMR (D₂O) δ17.5, 49.5,55.2, 71.4, 76.7, 79.0.

EXAMPLE 6

Tetra-O-acetyl-5-amino-5-deoxy-gluconic acid lactam. 13 The acetylatedoxime 9 (1.5 g, 3.84 mmol) was deacetylated with concomitant conversionto the acyl hydrazide by treatment with anhydrous hydrazine (0.75 ml,23.89 mmol) in methanol (15 ml) at room temperature for 2 hours.Evaporation of the solvent gave the crude acid hydrazide 12: ¹H NMR(D₂O) δ4.18 (1H, dd, J=4.6 Hz, J=7.0 Hz) 4.51 (1H, d, J=6.5 Hz), 4.43(1H, d, J=14.9 Hz), 4.53 (1H, d, J=14.8 Hz), 5.18 (1H, d, J=4.6 Hz); ¹³CNMR (D₂O) δ61.1, 69.1, 73.4, 73.5, 160.7, 173.4. This hydrazide 12 washydrogenated in glacial acetic acid with 10%, Pd/C (0.4 g) at 50° C. and300 psi pressure of H₂ for 2 days. After filtration through celite, thesolution was dried on the rotary evaporator and the crude productacetylated with acetic anhydride (15 ml) and pyridine (15 ml) for 5hours at room temperature. The mixture was poured into cold water andextracted with chloroform. The chloroform layer was dried with Na₂SO₄.Evaporation of the solvent gave crude product 13 (1.47 g), which wassubjected to flash chromatography on silica (eluent hexane-acetone =2:1)to give the perahydroxy lactam 13 (0.5 g) C-5 epimer: mp=177-178° C.;[δ]²³D+88.6° (c 1.11, CHCl₃), lit.+104° (c 1.73, CHCl₃) [17]; ¹H NMR(CDCl₃) δ2.03 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.08 (s, 3H, OAc), 2.10(s, 3H, OAc), 3.75 (ddd, 1H, J_(4,5) 9.7 Hz, J_(5,6)a2.9 Hz, J_(5,6b)6.5 Hz, H-5), 3.96 (dd, 1H, J_(6a,6b)11.7 Hz, H6-b), 4.22 (dd, 1H,H-6a), 5.06 (d, 1H, J_(3,2) 9.5 Hz, H-2), 5.20 (t, 1H, J_(3,4) 9.5 Hz,H-3), 5.53 (dd, 1H, H-4), 6.48 (s, 1H, s, NH); ¹³C NMR (CDCl₃) δ20.5,20.5, 20.5, 20.6, 52.4, 62.7, 67.2, 70.4, 70.5, 166.2, 169.4, 169.6,170.0, 170.4 HRMS (M+H⁺) calcd. 346.1060, found 346.1143. Epimer:[α]²³D+3.1° (c 1.81, CHCl₃); ¹H NMR (CDCl₃) 1.98 (s, 3H, OAc), 1.99 (s,3H, (OAC), 2.00 (2, 3H, OAC), 2.02 (s, 3H, OAC), 3.88 (1H, m, H-5), 4.04(dd, 1H, J_(6a,6b) 11.4 Hz, J_(5,6b) 6.3 Hz, H6-b), 4.18 (dd, 1H, J_(5,)_(6a) 3.9 Hz, H-6a), 5.15 (dd, 1H, J_(4,5) 9.5 Hz, J_(3,4) 7.5 Hz, H-4), 5.15 (d, 1H, J_(2,3) 7.5 Hz, H-2), 5.39 (t, 1H, H-3), 7.27 (1H, s,broad, NH); ¹³C NMR (CDCl₃) δ20.2, 20.3, 20.4, 50.0, 62.0, 68.0, 69.8,70.0, 166.7, 169.3, 169.7, 170.3, 170.6. The lactam 13 was converted tothe 1,5-diamino-1,5-dideoxy-D-glucitol (dideoxy-D-gluco)nojirimycin 14as in Example 5.

It will be appreciated that the imino group can contain a lower alkylgroup containing 1 to 6 carbon atoms rather than hydrogen. The oximegroup in compound 5 would then be an imino alkyl group, preferably wherealkyl contains 1 to 8 carbon atoms. The reactions are shown in FIG. 3.The hydrogen on the hexitol can be replaced with an alkyl group byreaction with an alkyl aldehyde and a reducing agent as shown in FIG. 4.

It is intended that the foregoing description be only illustrative ofthe present invention and that the present invention be limited only bythe hereinafter appended claims.

We claim:
 1. A process for the preparation of 1,5-imino,-1,5-dideoxyhexitol with protected hydroxyl groups which comprises: (a) reacting anacid ester of a 5-hexulosonic acid oxime or alkylimine with theprotected hydroxyl groups with hydrogen and a hydrogenation catalyst inan acidic solvent at a temperature between about 20 and 80° C. and apressure between about 200 and 400 psi to form a 5-imino-5-deoxyaldonicacid lactam; and (b) reducing and deprotecting the hydroxyl groups ofthe lactam with a reducing agent to form the 1,5-dideoxy-1,5-iminohexitol.
 2. The process of claim 1 wherein the acid ester is the theoxime.
 3. The process of claim 1 wherein the acid ester is thealkylimine.
 4. A process for the preparation of1,5-imino,-1,5-6-trideoxy hexitol as a product which comprises: (a)reacting methyl-2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime withhydrogen and a hydrogenation catalyst at a temperature between about 20and 80° C. and a pressure between about 200 and 400 psi in an acidicsolvent to form a 1,5,6-triacetoxy acid lactam; (b) reducing anddeacetylating the lactam with a reducing agent to form the 1,5-iminohexitol.
 5. The process of claim 4 wherein the 5-hexulosonic acid isL-xylo and hexitol is D-glucitol.
 6. The process of claim 4 wherein5-hexulosonic acid is L-arabino and hexitol is D-galactitol.